tbuckley/cabot-search huggingface dataset:
CD8+ T cells recognizing a neuron-restricted antigen injure axons in a model of multiple sclerosis
Authors: Benjamin D.S. Clarkson, Ethan M. Grund, Miranda M. Standiford, Kanish Mirchia, Maria S. Westphal, Liz S. Muschler, Charles L. Howe
Journal: Journal of Clinical Investigation (2023)

CD8+ T cells outnumber CD4+ cells in multiple sclerosis (MS) lesions associated with disease progression, but the pathogenic role and antigenic targets of these clonally expanded effectors are unknown. Based on evidence that demyelination is necessary but not sufficient for disease progression in MS, we previously hypothesized that CNS-infiltrating CD8+ T cells specific for neuronal antigens directly drive the axonal and neuronal injury that leads to cumulative neurologic disability in patients with MS. We now show that demyelination induced expression of MHC class I on neurons and axons and resulted in presentation of a neuron-specific neoantigen (synapsin promoter–driven chicken ovalbumin) to antigen-specific CD8+ T cells (anti-ovalbumin OT-I TCR-transgenic T cells). These neuroantigen-specific effectors surveilled the CNS in the absence of demyelination but were not retained. However, upon induction of demyelination via cuprizone intoxication, neuroantigen-specific CD8+ T cells proliferated, accumulated in the CNS, and damaged neoantigen-expressing neurons and axons. We further report elevated neuronal expression of MHC class I and β2-microglobulin transcripts and protein in gray matter and white matter tracts in tissue from patients with MS. These findings support a pathogenic role for autoreactive anti-axonal and anti-neuronal CD8+ T cells in MS progression.
Translated impact on carbon footprint from choice of inhaled therapy: a Danish scenario
Authors: Jørgen Vestbo, Kåre Press-Kristensen
Journal: European Respiratory Journal (2023)

With increasing climate change, all sources of greenhouse gases must be considered. Hydrofluorocarbon (HFC) propellants are used in all pressurised metered dose inhalers (pMDIs) and, although they are not as ozone-depleting as the earlier chlorofluorocarbons (CFCs), they are potent greenhouse gases and there is a general ask for reduction in their use [1]. In this respect, respiratory doctors indirectly affect climate change through their prescription patterns [2], something only few are aware of, and which may be difficult to translate and explain to patients. To illustrate the impact of switching from pMDIs to dry powder inhalers (dMDIs) we wanted to compare climate impact of inhaler switching to climate costs of well-known items and activities in Denmark, a country with a population of 6 million inhabitants. Carbon footprint of MDIs can be translated into measures that are intuitive to both patients and health professionals https://bit.ly/45iVbHC
European Respiratory Society short guidelines for the use of as-needed ICS/formoterol in mild asthma
Authors: Alberto Papi, Diogenes S. Ferreira, Ioana Agache, Eugenio Baraldi, Richard Beasley, Guy Brusselle, Courtney Coleman, Mina Gaga, Carolina Maria Gotera Rivera, Erik Melén, Ian D. Pavord, Deborah Peñate Gómez, Daniel Schuermans, Antonio Spanevello, Thomy Tonia, Florence Schleich
Journal: European Respiratory Journal (2023)

Recent clinical trials of as-needed fixed-dose combination of inhaled corticosteroid (ICS)/formoterol have provided new evidence that may warrant a reconsideration of current practice. A Task Force was set up by the European Respiratory Society to provide evidence-based recommendations on the use of as-needed ICS/formoterol as treatment for mild asthma. The Task Force defined two questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The Task Force utilised the outcomes to develop recommendations for a pragmatic guideline for everyday clinical practice. The Task Force suggests that adults with mild asthma use as-needed ICS/formoterol instead of regular ICS maintenance treatment plus as-needed short-acting β 2 -antagonist (SABA) and that adolescents with mild asthma use either as-needed ICS/formoterol or ICS maintenance treatment plus as-needed SABA (conditional recommendation; low certainty of evidence). The recommendation for adults places a relatively higher value on the reduction of systemic corticosteroid use and the outcomes related to exacerbations, and a relatively lower value on the small differences in asthma control. Either treatment option is suggested for adolescent patients as the balance is very close and data more limited. The Task Force recommends that adult and adolescent patients with mild asthma use as-needed ICS/formoterol instead of as-needed SABA (strong recommendation; low certainty of evidence). This recommendation is based on the benefit of as-needed ICS/formoterol in mild asthma on several outcomes and the risks related to as-needed SABA in the absence of anti-inflammatory treatment. The implementation of this recommendation is hampered in countries (including European Union countries) where as-needed ICS/formoterol is not approved for mild asthma.
From pre-COPD to COPD: a Simple, Low cost and easy to IMplement (SLIM) risk calculator
Authors: Miguel J. Divo, Congjian Liu, Francesca Polverino, Peter J. Castaldi, Bartolome R. Celli, Yohannes Tesfaigzi
Journal: European Respiratory Journal (2023)

Background The lifetime risk of developing clinical COPD among smokers ranges from 13% to 22%. Identifying at-risk individuals who will develop overt disease in a reasonable timeframe may allow for early intervention. We hypothesised that readily available clinical and physiological variables could help identify ever-smokers at higher risk of developing chronic airflow limitation (CAL). Methods Among 2273 Lovelace Smokers’ Cohort (LSC) participants, we included 677 (mean age 54 years) with normal spirometry at baseline and a minimum of three spirometries, each 1 year apart. Repeated spirometric measurements were used to determine incident CAL. Using logistic regression, demographics, anthropometrics, smoking history, modified Medical Research Council dyspnoea scale, St George's Respiratory Questionnaire, comorbidities and spirometry, we related variables obtained at baseline to incident CAL as defined by the Global Initiative for Chronic Obstructive Lung Disease and lower limit of normal criteria. The predictive model derived from the LSC was validated in subjects from the COPDGene study. Results Over 6.3 years, the incidence of CAL was 26 cases per 1000 person-years. The strongest independent predictors were forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) &lt;0.75, having smoked ≥30 pack-years, body mass index (BMI) ≤25 kg·m 2 and symptoms of chronic bronchitis. Having all four predictors increased the risk of developing CAL over 6 years to 85% (area under the receiver operating characteristic curve (AUC ROC) 0.84, 95% CI 0.81–0.89). The prediction model showed similar results when applied to subjects in the COPDGene study with a follow-up period of 10 years (AUC ROC 0.77, 95% CI 0.72–0.81). Conclusion In middle-aged ever-smokers, a simple predictive model with FEV 1 /FVC, smoking history, BMI and chronic bronchitis helps identify subjects at high risk of developing CAL.
Dynamical modeling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity
Authors: Seemadri Subhadarshini, Sarthak Sahoo, Shibjyoti Debnath, Jason A Somarelli, Mohit Kumar Jolly
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Phenotypic heterogeneity of melanoma cells contributes to drug tolerance, increased metastasis, and immune evasion in patients with progressive disease. Diverse mechanisms have been individually reported to shape extensive intra-tumor and inter-tumor phenotypic heterogeneity, such as IFNγ signaling and proliferative to invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. Methods Here, we integrate dynamical systems modeling with transcriptomic data analysis at bulk and single-cell levels to investigate underlying mechanisms behind phenotypic heterogeneity in melanoma and its impact on adaptation to targeted therapy and immune checkpoint inhibitors. We construct a minimal core regulatory network involving transcription factors implicated in this process and identify the multiple ‘attractors’ in the phenotypic landscape enabled by this network. Our model predictions about synergistic control of PD-L1 by IFNγ signaling and proliferative to invasive transition were validated experimentally in three melanoma cell lines—MALME3, SK-MEL-5 and A375. Results We demonstrate that the emergent dynamics of our regulatory network comprising MITF, SOX10, SOX9, JUN and ZEB1 can recapitulate experimental observations about the co-existence of diverse phenotypes (proliferative, neural crest-like, invasive) and reversible cell-state transitions among them, including in response to targeted therapy and immune checkpoint inhibitors. These phenotypes have varied levels of PD-L1, driving heterogeneity in immunosuppression. This heterogeneity in PD-L1 can be aggravated by combinatorial dynamics of these regulators with IFNγ signaling. Our model predictions about changes in proliferative to invasive transition and PD-L1 levels as melanoma cells evade targeted therapy and immune checkpoint inhibitors were validated in multiple RNA-seq data sets from in vitro and in vivo experiments. Conclusion Our calibrated dynamical model offers a platform to test combinatorial therapies and provide rational avenues for the treatment of metastatic melanoma. This improved understanding of crosstalk among PD-L1 expression, proliferative to invasive transition and IFNγ signaling can be leveraged to improve the clinical management of therapy-resistant and metastatic melanoma.
Derivation of a high-resolution CT-based, semi-automated radiographic score in tuberculosis and its relationship to bacillary load and antitubercular therapy
Authors: Catherine Riou, Elsa du Bruyn, Grace Hyun J. Kim, Irene da Costa, Jihey Lee, Alan Sher, Robert J. Wilkinson, Brian W. Allwood, Jonathan Goldin
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>A high-resolution CT based, semi-automated radiographic score correlates with <i>Mycobacterium tuberculosis</i> (Mtb) bacterial burden, peripheral monocyte count and the phenotypic profile of Mtb-specific CD4 T-cells, irrespective of HIV status</b>https://bit.ly/44do4V6
Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival
Authors: Zeguo Sun, Zhongyang Zhang, Khadija Banu, Ian W. Gibson, Robert B. Colvin, Zhengzi Yi, Weijia Zhang, Bony De Kumar, Anand Reghuvaran, John Pell, Thomas D. Manes, Arjang Djamali, Lorenzo Gallon, Philip J. O’Connell, John Cijiang He, Jordan S. Pober, Peter S. Heeger, Madhav C. Menon
Journal: Journal of Clinical Investigation (2023)

Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-β1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-β1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-β1-dependent effects on T cells.
Reduced Odds of Mpox-Associated Hospitalization Among Persons Who Received JYNNEOS Vaccine — California, May 2022–May 2023
Authors: Samuel Schildhauer, Kayla Saadeh, Josh Vance, Joshua Quint, Tarek Salih, Timothy Lo, Awa Keinde, Edwin Chojolan, Esther Gotlieb, Marisa Ramos, Eric Chapman, Philip Peters, Jessica Watson, Kelly A. Johnson, Eric C. Tang, Kathleen Jacobson, Robert Snyder
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

The effectiveness of 1 dose of JYNNEOS vaccine (modified vaccinia Ankara vaccine, Bavarian Nordic) against hospitalization for mpox (caused by Monkeypox virus), has been demonstrated; however, the impact of 2 doses on hospitalization risk, especially among persons infected with HIV, who are at higher risk for severe disease, is an important factor in evaluating vaccine effectiveness against mpox disease severity and Monkeypox virus infection. Surveillance data collected by the California Department of Public Health were used to evaluate whether receipt of 2 doses of JYNNEOS vaccine reduced the odds of hospitalization among persons with mpox. The odds of hospitalization among persons with mpox who had received 1 or 2 JYNNEOS doses were 0.27 (95% CI = 0.08-0.65) and 0.20 (95% CI = 0.01-0.90), respectively, compared with unvaccinated mpox patients. In mpox patients with HIV infection, the odds of hospitalization among those who had received 1 JYNNEOS vaccine dose was 0.28 (95% CI = 0.05-0.91) times that of those who were unvaccinated. No mpox-associated hospitalizations were identified among persons infected with HIV who had received 2 JYNNEOS vaccine doses. To optimize durable immunity, all eligible persons at risk for mpox, especially those infected with HIV, should complete the 2-dose JYNNEOS series.
Regular, low-dose, sustained-release morphine for persisting breathlessness in interstitial lung disease: a randomised, double-blind, placebo-controlled, crossover trial
Authors: Diana H. Ferreira, Magnus Ekström, Sabrina Bajwah, Belinda Fazekas, David C. Currow
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>In this trial of low-dose, sustained-release morphine for breathlessness in ILD there was no clear signal of improvement; morphine was associated with more harms. Predictors of response and factors influencing perception of benefit need to be identified.</b>https://bit.ly/45TM7Jf
Outbreak of Locally Acquired Mosquito-Transmitted (Autochthonous) Malaria — Florida and Texas, May–July 2023
Authors: Dawn Blackburn, Michael Drennon, Kelly Broussard, Andrea M. Morrison, Danielle Stanek, Elizabeth Sarney, Christina Ferracci, Steve Huard, Wade Brennan, John Eaton, Sara Nealeigh, Natalie Barber, Rebecca A. Zimler, Jeremy N. Adams, Carina Blackmore, Manuel Gordillo, Robert Mercado, Harold Vore, Kelly Scanlan, Ian Motie, Leslie Stanfield, Ahmed Farooq, Kimberly Widel, Kelly Tomson, Nancy Kerr, John Nasir, Marshall Cone, Connor Rice, Thomas Larkin, Edwin Hernandez, Jennifer Bencie, Christopher R. Lesser, Max Dersch, Samantha Ramirez-Lachmann, Marah Clark, Susan Rollo, Amira Bashadi, Ronald Tyler, Bethany Bolling, Brent Moore, Brendan Sullivan, Eric Fonken, Raquel Castillo, Yaziri Gonzalez, Gustavo Olivares, Kimberly E. Mace, Dean Sayre, Audrey Lenhart, Alice Sutcliffe, Ellen Dotson, Claudia Corredor, Emma Rogers, Brian H. Raphael, Sarah G. H. Sapp, Yvonne Qvarnstrom, Alison D. Ridpath, Peter D. McElroy
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Eight cases of locally acquired, mosquito-transmitted (i.e., autochthonous) Plasmodium vivax malaria, which has not been reported in the United States since 2003, were reported to CDC from state health departments in Florida and Texas during May 18-July 17, 2023. As of August 4, 2023, case surveillance, mosquito surveillance and control activities, and public outreach and education activities continue in both states. U.S. clinicians need to consider a malaria diagnosis in patients with unexplained fever, especially in areas where autochthonous malaria has been recently reported, although the risk for autochthonous malaria in the United States remains very low. Prompt diagnosis and treatment of malaria can prevent severe disease or death and limit ongoing transmission to local Anopheles mosquitoes and other persons. Preventing mosquito bites and controlling mosquitoes at home can prevent mosquitoborne diseases, including malaria. Before traveling internationally to areas with endemic malaria, travelers should consult with a health care provider regarding recommended malaria prevention measures, including potentially taking malaria prophylaxis. Malaria is a nationally notifiable disease; continued reporting of malaria cases to jurisdictional health departments and CDC will also help ensure robust surveillance to detect and prevent autochthonous malaria in the United States.
ChromGene: gene-based modeling of epigenomic data
Authors: Artur Jaroszewicz, Jason Ernst
Journal: Genome biology (2023)

Various computational approaches have been developed to annotate epigenomes on a per-position basis by modeling combinatorial and spatial patterns within epigenomic data. However, such annotations are less suitable for gene-based analyses. We present ChromGene, a method based on a mixture of learned hidden Markov models, to annotate genes based on multiple epigenomic maps across the gene body and flanks. We provide ChromGene assignments for over 100 cell and tissue types. We characterize the mixture components in terms of gene expression, constraint, and other gene annotations. The ChromGene method and annotations will provide a useful resource for gene-based epigenomic analyses.
Transcriptional immunogenomic analysis reveals distinct immunological clusters in paediatric nervous system tumours
Authors: Arash Nabbi, Pengbo Beck, Alberto Delaidelli, Derek A. Oldridge, Sumedha Sudhaman, Kelsey Zhu, S. Y. Cindy Yang, David T. Mulder, Jeffrey P. Bruce, Joseph N. Paulson, Pichai Raman, Yuankun Zhu, Adam C. Resnick, Poul H. Sorensen, Martin Sill, Sebastian Brabetz, Sander Lambo, David Malkin, Pascal D. Johann, Marcel Kool, David T. W. Jones, Stefan M. Pfister, Natalie Jäger, Trevor J. Pugh
Journal: Genome Medicine (2023)

Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinants of immune response, the immune composition of paediatric solid tumours remains relatively uncharacterized calling for investigations to identify potential immune biomarkers. To inform immunotherapy approaches in paediatric cancers with embryonal origin, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve paediatric nervous system tumours (pedNST) spanning 12 cancer types from three publicly available data sets. Within pedNST, we uncovered four broad immune clusters: Paediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Desert (17%). We validated these clusters using immunohistochemistry, methylation immune inference and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters. Given the heterogeneity of immune infiltration within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies.
Breast cancer pre-clinical screening using infrared thermography and artificial intelligence: a prospective, multicentre, diagnostic accuracy cohort study
Authors: Xuefei Wang, Kuanyu Chou, Guochao Zhang, Zhichao Zuo, Ting Zhang, Yidong Zhou, Feng Mao, Yan Lin, Songjie Shen, Xiaohui Zhang, Xuejing Wang, Ying Zhong, Xue Qin, Hailin Guo, Xiaojie Wang, Yao Xiao, Qianchuan Yi, Cunli Yan, Jian Liu, Dongdong Li, Wei Liu, Mengwen Liu, Xiaoying Ma, Jiangtao Tao, Qiang Sun, Jidong Zhai, Likun Huang
Journal: International Journal of Surgery (2023)

Given the limited access to breast cancer (BC) screening, the authors developed and validated a mobile phone-artificial intelligence-based infrared thermography (AI-IRT) system for BC screening.This large prospective clinical trial assessed the diagnostic performance of the AI-IRT system. The authors constructed two datasets and two models, performed internal and external validation, and compared the diagnostic accuracy of the AI models and clinicians. Dataset A included 2100 patients recruited from 19 medical centres in nine regions of China. Dataset B was used for independent external validation and included 102 patients recruited from Langfang People's Hospital.The area under the receiver operating characteristic curve of the binary model for identifying low-risk and intermediate/high-risk patients was 0.9487 (95% CI: 0.9231-0.9744) internally and 0.9120 (95% CI: 0.8460-0.9790) externally. The accuracy of the binary model was higher than that of human readers (0.8627 vs. 0.8088, respectively). In addition, the binary model was better than the multinomial model and used different diagnostic thresholds based on BC risk to achieve specific goals.The accuracy of AI-IRT was high across populations with different demographic characteristics and less reliant on manual interpretations, demonstrating that this model can improve pre-clinical screening and increase screening rates.
Gene-activated hyaluronic acid-based cryogels for cartilage tissue engineering
Authors: Natalia Carballo-Pedrares, Junquera López-Seijas, Diego Miranda-Balbuena, Ibán Lamas, Julián Yáñez, Ana Rey-Rico
Journal: Journal of Controlled Release (2023)

Articular cartilage injuries are very frequent lesions that if left untreated may degenerate into osteoarthritis. Gene transfer to mesenchymal stem cells (MSCs) provides a powerful approach to treat these lesions by promoting their chondrogenic differentiation into the appropriate cartilage phenotype. Non-viral vectors constitute the safest gene transfer tools, as they avoid important concerns of viral systems including immunogenicity and insertional mutagenesis. However, non-viral gene transfer usually led to lower transfection efficiencies when compared with their viral counterparts. Biomaterial-guided gene delivery has emerged as a promising alternative to increase non-viral gene transfer efficiency by achieving sustained delivery of the candidate gene into cellular microenvironment. In the present study, we designed hyaluronic acid-based gene-activated cryogels (HACGs) encapsulating a novel formulation of non-viral vectors based on niosomes (P80PX) to promote MSCs in situ transfection. The developed HACG P80PX systems showed suitable physicochemical properties to promote MSCs in situ transfection with very low cytotoxicity. Incorporation of a plasmid encoding for the transcription factor SOX9 (psox9) into HACG P80PX systems led to an effective MSCs chondrogenic differentiation with reduced expression of fibrocartilage and hypertrophic markers. The capacity of the developed systems to restore cartilage extracellular matrix was further confirmed in an ex vivo model of chondral defect.